CN1245536A - 新型钙蛋白酶,其制备和用途 - Google Patents
新型钙蛋白酶,其制备和用途 Download PDFInfo
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- CN1245536A CN1245536A CN97181646A CN97181646A CN1245536A CN 1245536 A CN1245536 A CN 1245536A CN 97181646 A CN97181646 A CN 97181646A CN 97181646 A CN97181646 A CN 97181646A CN 1245536 A CN1245536 A CN 1245536A
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Abstract
披露了新型钙蛋白酶及其制备,以及筛选新型钙蛋白酶抑制剂的方法及该抑制剂的用途。
Description
本发明涉及新型钙蛋白酶及其制备。本发明还涉及筛选新型钙蛋白酶抑制剂的方法及其用途。
钙蛋白酶属于半胱氨酸蛋白酶类的细胞内非溶酶体酶。这种酶参与真核细胞中的Ca2+-决定型信号转导,即它能根据Ca2+的浓度控制细胞功能。钙蛋白酶普遍存在于诸如人、鸡、兔或大鼠的动物组织和细胞中。钙蛋白酶还存在于诸如果蝇(Drosophila melanogaster)或Caenorhabditis elegans的低等动物中。尚未在酵母、真菌或细菌中检测到钙蛋白酶。
到目前为止,已知这种遍在钙蛋白酶有三种主要同种型,在体外可以通过钙决定型活性区分这三种同种型。钙蛋白酶I(=μ钙蛋白酶)是由μ-摩尔钙离子浓度激活的,而钙蛋白酶II(=m钙蛋白酶)能由毫摩尔浓度的钙离子激活。以上两种钙蛋白酶均由两个亚基组成。一个大的亚基大约为80kDa,而一个小亚基大约为30kDa。活性异源双体的两个亚基均具有钙结合位点。所述大亚基由以下四个蛋白域(=I-IV)组成:蛋白酶域(=域II),钙结合域(=域IV)和两个其它域(=域I和III),这两个域的功能尚不清楚。所述小的30K亚基由一个钙结合亚基(=IV’)和另一个其功能尚不清楚的亚基(=V)组成。除了以上两种类型的钙蛋白酶外,在鸡体内发现了第三种类型,该类型就钙活性而言是中间型(=μ/m 80K)(Wang K.K.W.等,TiPS,第15卷,1994:412-419,Suzuki,K等,Biol.Chem.Hoppe-Seyler,第376卷,1995:523-529)。
除了以上遍在钙蛋白酶之外,最近又鉴定了两种新的钙蛋白酶,这两种钙蛋白酶的表达是组织特异性的。nCL-1(=p94)是一种肌肉专一性钙蛋白酶,它存在于鸡、大鼠和人体内,推测其单体形式可具有活性,并且仅由80kd亚基组成。除了nCL-1之外,还有一种胃专一性钙蛋白酶,这种蛋白酶能以两种剪接变体nCL-2和nCL-2’出现。nCL-2’与nCL-2的区别在于它缺少钙结合区域(Sorimachi,H.S.等,生物化学杂志,第268卷,No.26,1993:19476-19482,Sorimachi,H.S.等,FEBS通讯,343,1994:1-5)。在果蝇属中还发现了一种钙蛋白酶同源蛋白(=CalpA),这种蛋白能与肌动蛋白相互作用,因此,推测其在胚胎发育中起着重要作用,这种蛋白具有两种不同的剪接变体(分子细胞生物学,第15卷,No.2,1995:824-834)。同样,在这种情况下,较短的变体也缺少钙结合位点。
据推测,钙蛋白酶在各种生理学过程中起着重要作用。大量的细胞骨架,诸如蛋白-激酶C、磷脂酶C、血影蛋白的膜结合蛋白或调节蛋白,诸如MAP2的细胞骨架蛋白,肌蛋白,神经丝和神经肽,血小板蛋白,表皮生长因子,NMDA受体和参与有丝分裂的蛋白,以及其它蛋白都是钙蛋白酶底物(Barrett M.J.等,生命科学48,1991:1659-69,Wang K.K.等,药理科学动态,15,1994:412-419)。钙蛋白酶的正常生理学功能目前仍不十分了解。
在各种病理学过程和疾病中检测到了较高水平的钙蛋白酶,例如以下疾病:心脏的局部缺血(例如,心肌梗死),肾或中枢神经系统的局部缺血(例如,中风),发炎,肌肉萎缩症,眼部白内障(灰色白内障),中枢神经系统损伤(例如,创伤),阿尔茨海默氏病,HIV-诱导的神经病,帕金森氏和亨廷顿氏[Huntigton’s]病等。(参见上述Wang K.K.)据推测,以上疾病与较高的和持续的细胞内钙水平相关。这会导致钙决定型过程的过分活动,这些过程随后就不再受生理调节了。因此,钙蛋白酶的过分活动也可能导致病理学过程。
因此,人们推测钙蛋白酶的抑制剂能用于治疗上述疾病。各种研究都证实了这种推测。因此,Seung-Chyul Hong等(中风1994,25(3),663-669)和Bartus R.T.等(神经学研究,1995,17,249-258)证实,钙蛋白酶抑制剂对在中风以后发生的急性神经变性疾病具有神经保护作用。类似地,钙蛋白酶抑制剂可以改善在实验性脑创伤之后出现的记忆缺陷和神经运动紊乱的恢复(Saatman K.E.等,Proc.Natl.Acad.Sci.USA,93,1996:3428-3433)。Edelstein C.L.等(Proc.Natl.Acad.Sci.USA,92,1995,7662-7666)发现了钙蛋白酶抑制剂对低氧损伤肾的保护作用。Yoshyda K.I.等(日本循环系统杂志59(1),1995,40-48)能够证实在由局部缺血或再输注引起的心脏损伤之后,钙蛋白酶抑制剂的治疗作用。由于钙蛋白酶抑制剂能抑制β-AG4蛋白的释放,有人已提出了将其用于治疗阿尔茨海默氏病(Higaki J.等,神经元,14,1995:651-659)。钙蛋白酶抑制剂同样能抑制白介素-1α的释放(Watanabe N.等,细胞因子,6(6),1994:597-601)。还发现钙蛋白酶抑制剂对肿瘤细胞具有细胞毒性作用(Shiba E.等,第20届国际乳腺癌研究协会大会,日本仙台,1994年,9月25-28日,国际癌基因杂志5(增刊),1994,381)。钙蛋白酶还在再狭窄和关节炎中起着重要作用,因此,钙蛋白酶抑制剂对这类病具有治疗作用(March K.L.等,循环研究72,1993:413-423,Suzuki K.等,生物化学杂志285,1992:857-862)。
在Wang K.K.的著述中披露了钙蛋白酶抑制剂的其它可能用途(药理科学动态,15,1994:412-419)。
最有效的和选择性的钙蛋白酶抑制剂是天然存在的细胞内蛋白钙蛋白酶抑制蛋白。这种抑制剂能抑制钙蛋白酶I和钙蛋白酶II,但不能抑制其它半胱氨酸蛋白酶或巯基蛋白酶,如组织蛋白酶B、L或木瓜蛋白酶。不过,由大约700个氨基酸组成的抑制蛋白的缺陷是,由于它的大小和不能通过细胞膜,它不适用于可能的疗法。除了小分子量肽类的钙蛋白酶抑制剂外,还鉴定了多种非肽抑制剂。这些抑制剂的缺陷是,它们不稳定,会被迅速代谢,而且在某些场合下还具有毒性。此外,很多钙蛋白酶抑制剂还具有不充分的选择生,即它们不仅能抑制钙蛋白酶抑制剂I和II,而且还能抑制其它半胱氨酸蛋白酶,如木瓜蛋白酶,胰凝乳蛋白酶,弹性蛋白酶或组织蛋白酶B和L。
因此,仍然存在对选择性的、高度有效的钙蛋白酶抑制剂的需求。需要对于待鉴定的选择性抑制剂具有高度专一的实验系统,以便筛选所述选择性的、高度有效的钙蛋白酶抑制剂。所述筛选实验通常是通过遍在钙蛋白酶I和II实现的。
为了发现选择性抑制剂,有必要而且希望对其它钙蛋白酶进行试验,如果可能,这些钙蛋白酶是以组织专一性方式表达的,这样,就可以检验所述抑制剂在不同钙蛋白酶之间的选择性。
另外,其它新型钙蛋白酶是热门(gesuchte)蛋白,因为其在不同病理学或疾病中的表达很可能是不同的,并且在这些病中起着重要作用。
本发明的一个目的是提供了解和鉴定钙蛋白酶抑制剂的方法,该方法可以鉴定钙蛋白酶抑制剂,一方面,该抑制剂仅对一种钙蛋白酶具有抑制作用,另一方面,该抑制剂对几种钙蛋白酶具有抑制作用,并将该抑制剂用于治疗目的。
我们已经发现,所述目的可以通过一种新型钙蛋白酶及其等位变体、类似物或衍生物实现。
本发明还涉及一种鉴定钙蛋白酶抑制剂的方法,其中,由序列1或序列6编码的钙蛋白酶nCL-3是从表达nCL-3酶的组织或细胞中提取的,检测到了试验物质对所述酶nCL-3的底物的裂解的抑制作用,而且在至少一种其它试验中,检测到了试验物质对所述钙蛋白酶I和/或II的底物的裂解的抑制作用,选择所述对至少一种钙蛋白酶具有抑制作用的试验物质,或不能抑制酶nCL-3,但能抑制钙蛋白酶I和/或II的实验物质,或选择能抑制酶nCL-3,但不能抑制钙蛋白酶I和/或II的实验物质,或能抑制nCL-3和钙蛋白酶I和/或II的实验物质。
本发明还涉及一种鉴定钙蛋白酶抑制剂的方法,该方法包括在细胞系统中测定试验物质对酶nCL-3或钙蛋白酶I和/或II裂解底物的抑制作用,并选择能够通过细胞膜并能抑制酶nCL-3和/或钙蛋白酶I和/或II的细胞内活性的试验物质。
将钙蛋白酶专一性引物和基因组DNA用于功能域的指纹分析(Boehm T.,癌基因8,1993:1385-1390),通过PCR技术产生钙蛋白酶-特异性序列标记,该标记优选含有内含子序列,以改善所述钙蛋白酶序列的分化。
在克隆编码nCL-3的基因时,使用表1中所列出的丰余PCR引物。
表1
用于克隆nCL-3的丰余PCR引物(=2930)名称 序列CAL1 5<<-tng gng att gtt ggc tnc t-3<<
c c t tCAL2 5<<-ctn gaa aaa gcn tat gcn aa-3<<
t g g cCAL3 5<<-ttt ngc ata ngc ttt ttc na-3<<
c g c cCAL4 5<<-gtn aaa ggn cat gcn tat ac-3<<
g c c tCAL5 5<<-gag tan gca tgn cct ttn ac-3<<
ta g cCAL6 5<<-ttn cgn aat ccn tgg gg-3<<
c c
aCAL7 5<<- ccc can gga ttn cgn aan cg - 3<<
g g
tCAL8 5<<-gat ggn gaa ttt tgg atg-3<<
c g cCAL9 5<<-gac atc caa aat tcn cca tc-3<<
ct g c gCAL10 5<<-nag att aca tat ttc na-3<<
a g g a c
g
可以用引物对Cal6和Cal9(参见表1)制备被命名为29/30的克隆(=2930)。该克隆编码一个基因,该基因的产物是一种被命名为nCL-3的新型钙蛋白酶。克隆29/30(=nCL-3或2930)的核酸序列如序列1所示。由该序列衍生的nCL-3钙蛋白酶的氨基酸序列如序列2所示。在考虑了现有的内含子的基础上推断的氨基酸序列表现为典型的钙蛋白酶标记,因为它们的同源性很低不可能将该蛋白酶归入μ钙蛋白酶、m钙蛋白酶、nCL-1或nCL-2的已知钙蛋白酶亚族(参见表2)。它与已知钙蛋白酶亚族的同源性示于图3中。钙蛋白酶nCL-3是一种新型的、以前未披露过的钙蛋白酶。
序列分析证实了半胱氨酸蛋白酶催化中心的三个典型的氨基酸残基(Cys81,His252和Asn284)。源于所述基因序列的75-86号氨基酸残基(QGQVGNCWFVAA)符合典型巯基蛋白酶的保守特征。
表2
小鼠nCL-3(=2930)和其它钙蛋白酶在氨基酸水平上的同源性(%)名称 %同源性线虫tra-3 34.5果蝇属CalpA 31.5鸡p94 31.2人p94 30.9小鼠p94 30.5大鼠p94 30.0鸡μ/m 28.8鸡m 27.8人m 27.3鸡μ 25.4猪p94 25.4大鼠m 24.4大鼠nCL-2 23.9线虫CPL1 23.6人μ 23.1血吸虫 21.7兔m 16.1猪m 15.8猪μ 15.6小鼠CAP4 13.7兔μ 12.9
序列5中所显示的内含子(109-514号核苷酸)是通过与cDNA比较确定的。
通过对诸如基因库nr和dbest的多种数据库中的小鼠29/30序列(nCL-3)进行比较,发现了与CalpA,Tra-3和被命名为EST01106人类cDNA克隆HHCPE79的人序列的同源性(参见图2)。检测所述DNA和氨基酸序列与非丰余核酸,蛋白和国家生物技术信息中心(http://ww.ncbi.nlm.nih.gov)的数据库进行比较。氨基酸序列的比较是由Clustal W完成的(Thomrson等,核酸研究22,1994,4673-468=)。
通过与其它钙蛋白酶比较(图2),发现nCL-3不仅具有截短了的域I,而且具有一个修饰过的C-末端,该末端与其它钙蛋白酶的域IV没有明显的同源性。该钙蛋白酶的Ca2+-结合位点的共有序列(被称为EF手)位于域IV部分。nCL-3缺少该Ca2+-结合位点,这可能意味着没有Ca2+与域IV结合,该蛋白是以另一种方式激活。它是唯一的缺少钙调蛋白-样域IV的脊椎动物钙蛋白酶。
CalpA是果蝇属的组织特异性表达钙蛋白酶同系物(Theopold V.等,分子细胞生物学,第15卷,No.2,1995:824-834)。它是在果蝇属的中枢神经系统的某些神经元中、在中肠的分散细胞中和血细胞中表达。业已发现了CalpA的两种不同剪接变体。较短的变体缺少钙蛋白酶特有的钙-结合位点。
CalpA和nCL-3在氨基酸水平上的同源性为31.5%(参见表2)。Tra-3参与了Caenorhabditis elegans的性别决定。在一连串的若干基因及其产物中,Tra-3起着决定caenorhabditis雄性或雌雄同体发育的作用(Kuwabara P.E.等,TIG,第8卷,No.5,1992:164-168)。Tra-3似乎参与了精子发生。
Tra-3和nCL-3在氨基酸水平上的同源性为30.5%(参见表2)。nCL-3可能也参与了性别决定。
nCL-3和其它钙蛋白酶之间的其它同源性在表2中示出。
最大的同源性存在于nCL-3和人部分序列EST01106之间。所述部分序列EST01106获自海马文库。对于它的功能一无所知(自然355,6361,1992:632-634)。有关它的全基因序列以及该序列是否是一种钙蛋白酶基因同样不清楚。
CalpA、Tra-3、EST01106和nCL-3之间的序列比较在图2中示出。
以人海马马拉松-备用(Marathon-Ready)cDNA(Clontech)为起点,通过Frohman等(Proc.Natl.Acad.Sci.USA,85,1988:8998-9002)和Edwards等(核酸研究19,1991,5227-5232)改进的RACE方法(=cDNA末端的快速扩增),使用上述引物(Cal6和Cal9)可以克隆所述克隆(EST01106)的全序列。不过,起初不能用Clontech试剂盒的反向引物克隆其3’部分。仅利用互补于人EST序列的引物和互补于小鼠nCL-3序列的最后6个氨基酸的cDNA序列(5’-tcagacagccgtgagagagg-3’)的反向引物即可克隆其3’末端。
由序列6的基因序列衍生的氨基酸序列(序列7)与小鼠nCL-3序列具有92.2%的同源性(参见图4)。这种相似性相当于氨基酸水平上的同源性为:人和小鼠m-钙蛋白酶之间为97%,人和小鼠p94之间为93.5%,以上结果是我们通过测序得出的。因此,EST01106很可能是小鼠nCL-3序列的人类直向同源物。图4中还示出了caenorhabditis tra-3,果蝇属CalpA,小鼠p94,小鼠m-钙蛋白酶,人μ-钙蛋白酶和大鼠nCL-2的序列。各种钙蛋白酶和nCL-3之间表现出一致性的氨基酸通过加点的形式示出。短线表示为了获得序列的最大一致性而引入的缺口。nCL-3和CalpA转录物的交替剪接产物的C-末端在相关的全序列的上方和下方示出,该序列始于不同序列的起始处。星号表示所有钙蛋白酶的保守残基。相当于寡核苷酸Cal6和Cal9的两个氨基酸序列通过加边框的形式示出。箭头表示相应的小鼠nCL-3 DNA的剪接位点。
图5表示各种钙蛋白酶的系统发育谱系。为了绘制该谱系所作的系统发育分析是通过排除了缺口的毗邻法完成的(Saitou等,分子生物学进展4,1987,406-425)。通过这种系统发育分析可以将脊椎动物钙蛋白酶分成6种不同类型(图5,右侧)。可将非脊椎动物钙蛋白酶作为nCL-3类型的近邻,或将其归入同一类型。这样,nCL-3基因就形成了其自身的钙蛋白酶类型,它与非脊椎动物钙蛋白酶的同源性大于与脊椎动物钙蛋白酶的同源性。水平直线长度与各种钙蛋白酶之间的系统发育距离成正比。垂直直线距离没有意义。用于绘制所述系统发育谱系的序列具有如下SWISSTROT和EMBL编号(入藏号):人m(P17655),μ(P07384),p94(P20807);大鼠m(K07009),nCL-2(D14480),p94(P16259);小鼠p94(X92523);鸡m(D38026),μ(D38027),μ/m(P00789),p94(D38028);线虫tra-3(U12921);果蝇属CalpA(Q11002)和Dm(X78555),血吸虫(P27730)。
nCL-3基因结构示于图6中。通过对基因组DNA和cDNA进行DNA序列比较,发现了存在于该基因的编码序列类的外显子/内含子剪接接点。在其编码序列内发现了11个内含子。首先用引物Cal6和Cal9扩增的基因组片段的位置,用括号标出。
图6b表示各种钙蛋白酶的剪接位点的位置。令人吃惊的是,nCL-3和tra3尽管具有较大程度的同源性,但没有共同的剪接位点。nCL-3和脊椎动物钙蛋白酶之间的某些剪接位点的位置的一致性表明这些基因具有共同的起源。鸡μ/m-钙蛋白酶基因中的最后的保守剪接位点上的问号表示,所公布的序列在该剪接位点部位与原始cDNA序列不一致。
除了在序列1的序列中示出的nCL-3基因之外,还鉴定了一种截短形式,并在序列3中示出。由截短的nCL-3基因衍生的氨基酸序列示于序列4中。该截短的nCL-3基因被命名为nCL-3’,它可能是由于另一种剪接所产生的。使用覆盖所述内含子旁侧区的引物(参见图6)对从dE17细胞中提取的mRNA进行半定量RT-PCR分析,证实了未剪接的产物占n-CL3 mRNA的大约0.5%。
本发明的新型钙蛋白酶nCL-3以不同的强度在多种组织中表达(图1)。在mRNA分析检测中清楚地发现,nCL-3是在皮肤、肾、心、肺、胸腺和肝中表达的。
nCL-3基因在人体内的表达强度也是不同的。在研究过的所有组织中都检测到了低水平的表达。高水平的表达出现在结肠、睾丸、肾、肝和气管中。
nCL-3基因位于小鼠的7号染色体上,而在人体中是位于11号染色体上。它位于所述人染色体的长臂的大约84cM(=厘摩)处。它距离μ-钙蛋白酶的作图位置为12-14cM(11q13)。可以将nCL-3作图于非常接近糖蛋白A基因处(11q13.5-q14)。
小鼠直向同源nCL-3基因位于小鼠7号染色体的44-53cM之间。
需要提高抑制剂鉴定专一性的方法,以鉴定选择性的钙蛋白酶抑制剂。在这方面,重要的是所选择的抑制剂仅能抑制所需要的钙蛋白酶,而不能抑制其它半胱氨酸蛋白酶,以此种方式干预生理学过程。
例如,有待实验其抑制活性的实验物质可以是化学物质,微生物或植物提取物。除了要实验其对nCL-3、钙蛋白酶I和/或II的抑制活性外,通常还要实验其对组织蛋白酶B或其它巯基蛋白酶的活性。
优选地,好的抑制剂应当仅对组织蛋白酶B、L,弹性蛋白酶、木瓜蛋白酶、胰凝乳蛋白酶或其它半胱氨酸蛋白酶有小的活性或无活性,但对钙蛋白酶I和II具有良好的活性。
用本发明的方法,通过本发明的新型钙蛋白酶nCL-3可以鉴定到这样的抑制剂:该抑制剂对不同钙蛋白酶,如钙蛋白酶I,II,nCL-1,nCL-2和/或nCL-3能有所区别的加以抑制。
各种抑制剂试验是这样进行的:
组织蛋白酶B试验
用一种类似于S.Hasnain等的方法(生物化学杂志1993,268,235-240)的方法测定组织蛋白酶B的抑制作用。
用待试验的化学物质制备2μl抑制剂溶液,将微生物或植物提取物和DSMO(终浓度:100μM至0.01μM)加入88μl组织蛋白酶B(源于人肝,由Calbiochem提供,用500μM的缓冲液稀释至5个单位)中。在室温下(=25℃)预培养该混合物60分钟,然后加入10μl 10mM的Z-Arg-Arg-pNA(用含有10%EMSO的缓冲液配制)启动反应。在微量滴定板读数器中、在405nm波长下监测反应30分钟。然后由最大梯度测定IC50。
钙蛋白酶I和II实验
用Hammarsten酪蛋白(Merck,Darmstadt)作底物通过比色试验研究所述钙蛋白酶抑制剂的活性。该试验是在微量滴定板中进行的,正如由Buroker-Kilgore和Wang在分析生物化学208,1993,387-392中所披露的。所使用的酶是从猪的红细胞中提取的钙蛋白酶I(0.04U/试验),和从猪的肾中提取的钙蛋白酶II(0.2U/试验),这两种蛋白酶是由Calbiochem提供的。将待试验的物质与所述酶一起在室温下培养60分钟,溶剂DMSO的浓度不超过1%。加入Bio-Rad着色剂,然后用SLT EAR400Easy Reader在595nm波长下测定光学密度。50%的酶活性是从在没有抑制剂的最大酶活性和在没有添加钙的条件下的酶活性下测定的光学密度获得的。
可以用Suc-Leu Tyr-AMC进一步测定钙蛋白酶抑制剂的活性。这种荧光测定法由Zhao zhao Li等披露于医学化学杂志36(1993)3472-3480中。
由于钙蛋白酶是细胞内半胱氨酸蛋白酶,为了阻止钙蛋白酶对细胞内蛋白的降解作用,钙蛋白酶抑制剂必须通过细胞膜。诸如E64和亮抑蛋白酶肽的某些已知钙蛋白酶抑制剂尽管是良好的钙蛋白酶抑制剂,但由于穿过细胞膜的能力较差,因此,仅对细胞有较弱的作用。因此,有理由进行检验潜在的钙蛋白酶抑制剂通过细胞膜的能力的其它试验,如人血小板试验。
用于测定钙蛋白酶抑制剂的细胞活性的血小板试验。
在血小板中由钙蛋白酶介导的蛋白降解作用是通过由Zhao zhaoLi等披露于医学化学杂志36(1993)3472-3480中披露的方法进行的。人血小板是从获自供体的新鲜柠檬酸钠血液中提取的,并用缓冲液(5mM HEPES,140mMNaCl和1mg/mlBSA,pH7.3)调节至107细胞/ml。
将血小板(0.1ml)与1μl各种浓度的潜在抑制剂(溶解于DMSO中)一起预培养5分钟。然后加入钙离子载体A23187(在测试中为1μM)和钙(在测试中为5mM),并在37℃再培养5分钟。进行一个离心步骤,然后将该血小板溶入SDS-PAGE加样缓冲液中,并在95℃煮沸5分钟,在8%的凝胶上分离蛋白。然后对肌动蛋白-结合蛋白(=ABP)和踝蛋白两种蛋白的降解作用进行定量光密度测定。在加入钙和离子载体之后,上述蛋白消失,并产生了分子量低于200kd的新带。在有或没有(作为对照)本发明抑制剂的条件下测定1/2最大酶活性。
诸如脑切片的组织碎片或细胞培养物同样适用于试验通过细胞膜的能力。
对nCL-3进行抑制的试验是在能表达该蛋白的细胞中进行的,而后者可以用一种特异抗体检测。如果用钙和适当的离子载体的物质刺激细胞,则有可能导致nCL-3的活化。Takaomi Saido在生物化学杂志11(1992),81-86中披露了在活化以后μ-钙蛋白酶的自溶转变,并用抗体进行检测。生产出了用于检测nCL-3的相应抗体。钙蛋白酶抑制剂能抑制所述自溶转变,而且,用抗体可以进行相应的定量化。
除了所述的体外试验外,正如所述细胞血小板试验,本领域技术人员所知的所有其它钙蛋白酶试验均适用,如用于抑制皮质神经元由谷氨酸诱导的细胞死亡的实验(Maulucci-Gedde M.A.等,神经科学杂质7,1987:357-368),抑制NT2细胞中由钙介导的细胞死亡的试验(Squier M.K.T.等,细胞生理学杂志,159,1994:229-237,Patel T.等,Faseb杂志590,1996:587-597)或分析组织样品中的蛋白降解产物,如血影蛋白,MAP2或Tau(Ami Arai等,脑研究,1991,555,276-280,James Brorson等,中风,1995,26,1259-1267)。
为了在体外试验nCL-3,从能表达这种酶的组织或细胞中纯化钙蛋白酶nCL-3或其动物或人的同系物,所述组织如肾、胸腺、肝、肺,或从含有nCL-3基因的至少一个基因拷贝和/或具有至少一个基因拷贝的载体的细胞或微生物中纯化,并将其用作粗提取物或用作纯化酶。
对本发明方法而言,各种钙蛋白酶抑制剂试验优选与通过潜在抑制剂抑制nCL-3酶活性的试验组合进行。被选择用于上述目的的抑制剂要么仅能抑制酶nCL-3,而不能抑制其它钙蛋白酶,要么相反,仅能抑制其它钙蛋白酶,而不能抑制酶nCL-3,或者能抑制酶nCL-3以及至少一种其它钙蛋白酶。另外,所述各种抑制剂试验是以如下方式进行的,除了检验试验物质对nCL-3、钙蛋白酶I和/或II的抑制作用以外,作为对照,还要在没有试验物质的情况下进行试验。通过这种试验设计可以方便地测定所述试验物质的抑制作用。
本发明的另一种方法将酶nCL-3用于筛选新的钙蛋白酶抑制剂,该抑制剂能抑制所有钙蛋白酶或单一的钙蛋白酶,如钙蛋白酶I、II,nCL-1、nCL-2或nCL-3。可用于上述目的的各种试验物质在试验系统中进行单独试验或平行试验。所述试验物质优选在平行自主试验系统中筛选其抑制作用。
一般,所有物质都适用于抑制剂实验。因此,举例来说,所述物质可以通过经典的化学合成,通过组合化学方法,通过微生物、动物或植物提取物产生。例如,微生物提取物是指发酵液,破碎的微生物细胞或生物转化以后的物质。细胞分离物也适用于所述实验。
适用于提取酶促活性基因产物的所有原核或真核表达系统均适用于克隆nCL-3基因或其动物同系物或其人类同系物。优选的表达系统是能在细菌、真菌或动物细胞中表达nCL-3基因序列的表达系统,特别优选能在昆虫细胞中表达。酶促活性基因产物是指nCL-3蛋白,这种蛋白在从诸如原核或真核细胞的表达生物中提取之后马上或在复性之后形成一种活性蛋白,这种活性蛋白能够裂解至少一种如上文所述的、已知的钙蛋白酶底物,或通过自催化作用裂解本身。
本领域技术人员所知的一切钙蛋白酶试验均适用于测定酶促活性,如上文所披露的用于试验钙蛋白酶I和II的体外试验,或诸如血小板试验的细胞试验。而且还可以使用基于比色测定(Buroker-Kilgore M.等,分析生物化学208,1993:387-392)或基于荧光测定的检测试验。
另外,nCL-3的酶促活性基因产物还指含有nCL-3基因催化中心的所有部分序列和/或nCL-3基因的其它序列和/或钙蛋白酶序列和/或具有酶促活性的其它序列。
宿主生物是指适合于作为宿主生物的一切原核或真核生物,例如,诸如大肠杆菌(E.coli)、枯草芽胞杆菌(Bacillus subtilis)、浅青紫链霉菌(Streptomyces lividans)、肉质链球菌(Streptococcus carnosus)的细菌,诸如酿酒酵母(Saccharomycescerevisiae)、粟酒裂殖酵母(Schizosaccharomyces pombe)的酵母,诸如黑曲霉(Aspergillus niger)的真菌,诸如草地粘虫细胞(Spodoptera frugiperda)、夜蛾细胞的昆虫细胞,或所有适用于病毒表达的其它昆虫细胞,或诸如CV1,COS,C127,3T3或CHO的动物细胞或人细胞。
表达系统是指诸如上文提到的表达生物和适用于该生物的载体的组合,所述载体如质粒、病毒或噬菌体,如T7 RNA聚合酶/启动子系统或具有λ噬菌体的调节序列的载体。
所述表达系统一词优选是指大肠杆菌及其质粒和噬菌体或杆状病毒系统和诸如草地粘虫的合适昆虫细胞的组合。
另外,其它3’和/或5’调节序列适用于按照本发明进行的对nCL-3基因的有利表达。
所述调节序列希望能使nCL-3基因进行特异表达。例如,这是指根据宿主生物,仅在诱导以后进行该基因的表达或超量表达,或它能立即表达和/或超量表达。
而且,所述调节序列和因子优选对nCL-3基因表达有促进作用,因此能加强该基因的表达。因此,所述调节因子的增强作用优选是在转录水平上发生的,这种增强是通过使用诸如启动子和/或增强子的强转录信号实现的。除此之外,还可以通过诸如改善mRNA的稳定性的方法增强翻译。
例如,增强子是指DNA序列,该DNA序列通过改善RNA聚合酶和DNA之间的相互作用导致nCL-3基因表达的增强。
可将一个或几个DNA序列插入nCL-3基因的上游和/或下游,有或没有上游启动子或有或没有调节基因,以使该基因存在于一个基因结构中。
通过增加nCL-3基因的拷贝数,可以进一步加强该基因的表达。为了增加nCL-3基因的拷贝数,在诸如CHO表达载体的系统中扩增该基因。另外,适于作为载体的还有pED系列载体-双顺反子载体-该载体还含有二氢叶酸还原酶的可扩增的标记基因。详细内容可以查阅当代分子生物学方法,第2卷,1994。
通过诸如诱变的方法对nCL-3基因或其动物同系物进行修饰,可以使nCL-3酶的活性与其原始酶相比有所提高,所述经典诱变方法如UV辐射或用化学诱变剂处理和/或通过诸如定点诱变的定向诱变,缺失,插入和/或取代方法进行修饰。例如,通过以如下方式修饰其催化中心可以提高所述酶的活性:使待裂解的酶被更迅速地转化。除了所述基因扩增外,还可以通过以下方法提高酶的活性:消除抑制酶的生物合成的因素和/或合成活性nCL-3蛋白而不是非活性蛋白。通过这种方法可以提供用于体外试验的大量的酶。
可以使用诸如PCR技术(分子克隆,Sambrok,Fritsch和Maniatis,冷泉港实验室出版社,第2版1989,第14章,1-35,ISBN0-87969-309-6和Saiki等,科学,239(1988),487ff)的技术优选由基因组DNA或cDNA克隆nCL-3或其动物同系物,而且,nCL-3的克隆优选使用基因组DNA,特别优选使用源于小鼠细胞或人细胞的基因组DNA。
适用于所述克隆的宿主生物的例子是所有大肠杆菌菌株,优选大肠杆菌菌株DH10B。适用于所述克隆的载体是所有适于在大肠杆菌中表达的载体(参见分子克隆,Sambrok,Fritsch和Maniatis,冷泉港实验室出版社,第2版1989,第14章,1-35,ISBN 0-87969-309-6)。合适的例子是源于pDR或pUC或穿梭载体的载体,而pBluescript是尤其适合的。
在提取和测序以后,可以获得具有编码序列2所示氨基酸序列的核苷酸序列的nCL-3基因或其等位变体[variantions]。等位变体是指nCL-3变体,他在氨基酸水平上具有60-100%的同源性,优选70-100%,特别优选80-100%。等位变体具体包括通过核苷酸的缺失、插入或取代而从序列1或序列6所示序列获得的功能性变体,该变体保留了nCL-3的活性。
举例来说,nCL-3的同系物是指动物同系物,截短了的序列,如nCL-3’(参见序列3),编码和非编码DNA序列的单链DNA或RNA,特别是反义RNA。
nCL-3衍生物的例子是这样的衍生物,通过酶促方法很难将其裂解(如果能裂解的话),如核酸磷酸酯或phosphothioates,其中所述核酸的磷酸基团已分别被磷酸酯或thioate基团所取代。
还可以通过插入、和/或缺失通过一个或几个核苷酸的改变对所述核苷酸序列上游的启动子进行修饰,而这种修饰不会损害该启动子的功能或效果。另外,还可以通过修饰其序列提高该启动子的效果或用同样源于异源生物的更有效的启动子完全取代它。
通过本发明方法鉴定的钙蛋白酶抑制剂适用于生产治疗选自下列一组的疾病的药物:心血管疾病、免疫学疾病、炎症、变态反应、神经病、神经变性疾病或诸如再狭窄的致癌疾病,关节炎,心脏,肾或中枢神经系统的局部缺血(例如,中风),发炎,肌肉萎缩,眼部白内障(灰色白内障),对中枢神经系统的损伤(例如,创伤)阿尔茨海默氏病,HIV-诱导的神经病,帕金森氏和亨廷顿氏[Huntigton’s]病。
本发明的nCL-3基因序列还优选适用于诊断疾病,例如诊断肌肉萎缩症或用于基因治疗。
实施例例1:克隆nCL-3基因
将源于ES E14小鼠细胞的基因组DNA用于克隆具有序列1的nCL-3基因。在克隆时使用引物CAL6和CAL9的5’-3’(=正向)和3’-5’(=反向)序列(参见表1),和如下PCR条件(分子克隆,Sambrok,Fritsch和Maniatis,冷泉港实验室出版社,第2版1989,第14章,1-35,ISBN 0-87969-309-6和Saiki等,科学,239(1988),487ff):250ng正向引物250ng反向引物1.5mMMgCl20.2mMdNTPS50mMKCl10nMTris pH9.01μg基因组DNA2个单位的Taq聚合酶。
共进行35轮PCR,在94℃的温度下保持45秒,在48℃下保持45秒,并在72℃下保持2分钟。
用酶EcoRV将所述nCL-3基因克隆到载体pBluescript(SK+)中(参见Holten等,核酸研究,第19卷,No5,1156ff)。按照Maniatis等的方法用含有克隆进去的nCL-3基因的pBluescript载体转化大肠杆菌菌株DH10B(分子克隆,Sambrok,Fritsch和Maniatis,冷泉港实验室出版社,第1卷,第2版1989,,第1卷,第1章,74-84,ISDN 0-87969-309-6和Saiki等,科学,239(1988),487ff)。
还可以用这种方法克隆序列6所示的人nCL-3基因序列,克隆可以从0.1ngcDNA或0.5μg基因组DNA开始。克隆混合物优选另外含有0.1%Triton X-100。例2:nCL-3基因在各种小鼠组织中的表达
为了进行表达,从pE12胚胎中和从小鼠的皮肤、肾、心、肺、脑、胸腺和小肠组织中提取mRNA。为了提取mRNA,将所述组织分散在液氮中,并再悬浮于10ml的溶液中,该溶液含有4M异硫氰酸胍,25mM柠檬酸钠,0.5%十二烷基肌氨酸钠,和72μl 2-巯基乙醇。然后混入1ml的乙酸钠(pH4.0),10ml水饱和的苯酚和2ml三氯甲烷。将该样品离心(5000xg,4℃)20分钟。弃沉淀物。在-20℃下用1体积的异丙醇从上清液中沉淀RNA(沉淀至少1小时),再次离心30分钟(19,000xg,4℃)。将沉淀重新悬浮于300μl溶液中,再次用乙酸钠/乙醇在冷却条件下沉淀,并用70%的乙醇沉淀,离心(19,000xg,4℃),洗涤并溶解于300μl水中。用光度计在250nm波长下测定mRNA的浓度,并用5μlmRNA样品在琼脂糖凝胶中进行电泳,与参照物进行比较。
通过RT-PCR测定nCL-3基因在各种小鼠组织中的表达,其中,用反转录酶以提取的mRNA为起点,通过以下两种引物首先产生cDNA拷贝:a)正向引物5’-tagctcgagtggacgtaatcgtcgatgac-3’b)反向引物5’-tagctcgagtgctgtaggctgtgcatacg-3’(参见图1)。
按照以下GIBCO方法制备cDNA:
将2μl寡聚(脱氧胸苷)和12μl DEPC蒸馏水加入5μg mRNA(通过上述方法提取)中。将该混合物在70℃下培养10分钟,然后放在冰上。依次向该样品中加入2μl 10X缓冲液,2μl 25mMMgCl2,1μl 10mM dNTPs,2μl 1M DTT。在23℃下培养5分钟,然后加入1μl Superscript逆转录酶,并将该混合物在25℃下再培养10分钟,在42℃下再培养50分钟,在70℃下再培养15分钟。然后加入1μl的RNAse H和79μl蒸馏水,并使反应在37℃下继续20分钟,在70℃下继续15分钟。将1μl所述cDNA用于所述RT-PCR反应。
所述用于检测nCL-3表达的PCR反应是通过如下方法进行的:250ng正向引物250ng反向引物1.5 MgCl20.2 dNTPS50 KCl10 Tris pH9.01μg cDNA2个单位的Taq聚合酶。
进行35轮PCR,在94℃的温度下保持45秒,在58℃下保持45秒,并在72℃下保持1分钟。
在试验过的组织中证实了nCL-3在dE12胚胎中的表达。nCL-3还能在皮肤、肾、心、肺和胸腺中表达。在脑和小肠中的表达比在上述器官中的表达弱(在图1中未示出)。所使用的内标是hprt(=次黄嘌呤磷酸核糖基转移酶)。例3:克隆人nCL-3序列
通过Frohman等(Proc.Natl.Acad.Sci.USA,85,1988:8998-9002)和Edwards等(核酸研究19,1991,5227-5232)披露的方法测定人或小鼠nCL-3 cDNA的3’末端。将人海马马拉松-备用cDNA(Clontech)用于所述人序列的5’和3’末端。对于小鼠序列而言,将12日龄的小鼠胚胎用于例2所述方法。用该试剂盒中的反向引物不能提取人3’末端。用互补于人EST序列的正向引物和相当于小鼠nCL-3序列的最后6个氨基酸的反向引物(5’-tcagacagccgtgagagagg-3’)成功地进行了克隆。例4:粘粒克隆的提取和鉴定
从一个粘粒文库中提取具有小鼠nCL-3基因的粘粒克隆,该粘粒文库是通过克隆在载体pSuperCos(stratagene)中而由基因组ES小鼠细胞DNA制备的。已将该文库分成348个库,每个库有1000个克隆。通过用nCL-3-特异引物进行的PCR分析鉴定阳性库。
将所述库铺平板并筛选。通过与32P-标记过的小鼠nCL-3cDNA片段进行菌落杂交鉴定阳性克隆。例5:RNA表达分析
通过让人RNA主印迹(Clontech)与32P-标记过的人nCL-3片段(1-928号核苷酸,编码1-295号氨基酸)杂交,研究人nCL-3的表达。所述杂交和高度严格的洗涤条件是按照生产商的推荐进行的。例6:将所述nCL-3基因定位于染色体上
所述基因在小鼠中的定位是通过对基因组DNA进行PCR分析完成的,所述基因组DNA是从小鼠X仓鼠体细胞杂合体中提取的,如由williamson等所披露的方法(哺乳动物基因组6,1995,429-432),使用由Schupp等所披露的一组DNA(免疫遗传学45,1997,180-187)。所使用的引物序列为5’-tgcacagcctacagcataag-3’和5’-tcagacagccgtgagagagg-3’。使用上述引物可以扩增一个大约2.7kb的小鼠片段,该片段没有仓鼠DNA。按照生产商的推荐,在58℃的退火温度下用扩增长模板PCR系统(Boehringer Mannheim)进行PCR反应。
所述基因在人体中的定位是使用NIGMS人/啮齿动物体细胞杂合体作图系列(Coriell Cell Repositories)完成的。将以下引物用作PCR反应的引物序列:5’-acttcatcttctggcttcttgacttc-3’和5’-gctgcatcaaccacaaggacac-3’。PCR扩增是在58℃的退火温度下进行的,得到了一种600bp的片段。对该结果进行检验,检查人染色体的存在和PCR产物之间的一致性。该基因在人染色体上的准确位置是这样找到的:使用Genebridge 4RH系列(Research Genetics),并将该PCR结果转移到Genome Research的MIF中心的定位机构(http://www/genome.wi.mit.edu)。例7:组织蛋白酶B实验
组织蛋白酶B的抑制作用是通过类似于由S.Hasnain等在生物化学杂志168(1993),235-40中披露的方法的方法测定的。将2μl由抑制剂和DMSO制备的抑制剂溶液(终浓度:100μM-0.01μM)加入88μl的组织蛋白酶B(组织蛋白酶B源于人肝(Calbiochem),用500μM的缓冲液稀释至5个单位)中。在室温(25℃)下预培养60分钟,然后通过加入10μl 10μM Z-Arg-Arg-pNA(用含有10%的DMSO的缓冲液配制)启动反应。在405nM的波长下在微量滴定板计数器中监测反应30分钟。然后由最大梯度测定IC50。例8:钙蛋白酶试验
用Hammarsten酪蛋白(Merck,Darmstadt)作底物通过比色试验研究所述钙蛋白酶抑制剂的活性。该试验是按照由Buroker-Kilgore和Wang在分析生物化学208,1993,387-392中所披露的方法在微量滴定板中进行的。所使用的酶是29/30,这种酶是在上述系统之一中表达的并经过纯化。将待试验的物质与所述酶一起在室温下培养60分钟,溶剂DMSO的浓度不超过1%。加入Bio-Rad着色剂,然后用SLT EAR400Easy Reader在595nm波长下测定光学密度。50%的酶活性是从在没有抑制剂的最大酶活性和在没有添加钙的条件下的酶活性下测定的光学密度获得的。例9:用于测定钙蛋白酶抑制剂的细胞活性的血小板试验。
在血小板中由钙蛋白酶介导的蛋白降解作用是通过由Zhao zhaoLi等披露于医学化学杂志36(1993)3472-3480中披露的方法进行的。人血小板是从获自供体的新鲜柠檬酸钠血液中提取的,并用缓冲液(5mM HEPES,140mMNaCl和1mg/mlBSA,pH7.3)调节至107细胞/ml。
将血小板(0.1ml)与1μl各种浓度的抑制剂(溶解于DMSO中)一起预培养5分钟。然后加入钙离子载体A23187(在测试中为1μM)和钙(在测试中为5mM),并在37℃再培养5分钟。进行一个离心步骤,然后将该血小板溶入SDS-PAGE加样缓冲液中,并在95℃煮沸5分钟,在8%的凝胶上分离蛋白。然后对肌动蛋白-结合蛋白(=ABP)和踝蛋白两种蛋白的降解作用进行定量光密度测定。在加入钙和离子载体之后,上述蛋白消失,并产生了分子量在200kd范围内的新带。由此测定1/2最大酶活性。
序列表(1)一般资料:(i)申请人:
(A)名称:BASF股份公司
(B)街道:卡尔波希大街
(C)城市:Ludwigshafen
(D)州或省:Rhineland-Palatinate
(E)国家:德国
(F)邮编:D-67056(ii)发明名称:新型钙蛋白酶,其制备和用途(iii)序列数:7(iv)计算机可读形式:
(A)媒体类型:软盘
(B)计算机:IBM PC兼容
(C)操作系统:PC-DOS/MS-DOS
(D)软件:PatentIn Release#1.0,Version#1.25(EPO)(2)序列1资料:(i)序列特征:
(A)长度:2459个碱基对
(B)类型:核酸
(C)链型:单
(D)拓扑结构:线形(ii)分子类型:cDNA(iii)假说:无(iii)反义:无(vi)来源:
(A)生物:小家鼠(Mus musculus)(ix)特征
(A)名称/键:5’UTR
(B)位置:1..193(ix)特征
(A)名称/键:3’UTR
(B)位置:2117..2459(ix)特征
(A)名称/键:CDS
(B)位置:194..2116(xi)序列描述:序列1:CTGAAGCCCG GGGGTCCAAG TTCCAACCCC CGCCTGCGGG CTGCCGGGGT ATCATCTCCC 60CGCAGAGTCC CGGCCGTGGC GCGGGCTGGT CTAGCCTCCG CTCCAGTGCC CGCACTGTGC 120TCTGCATCCC GGGAGTCCAG CTCCAGCTGC GGCGACGCGG CAGGTGCCTC CCCTTCTTGG 180GGACGTGGTC ACC ATG TTC TCC TGC GCG AAG GCC TAT GAG GAC CAG AAC 229
Met Phe Ser Cys Ala Lys Ala Tyr Glu Asp Gln Asn
1 5 10TAC TCG GCG CTG AAG CGG GCC TGC CTG CGC AAG AAG GTG CTG TTC GAG 277Tyr Ser Ala Leu Lys Arg Ala Cys Leu Arg Lys Lys Val Leu Phe Glu
15 20 25GAT CCC CTC TTC CCT GCC ACC GAC GAC TCC CTT TAC TAT AAG GGC ACC 325Asp Pro Leu Phe Pro Ala Thr Asp Asp Ser Leu Tyr Tyr Lys Gly Thr
30 35 40CCA GGG CCC ACA GTC AGG TGG AAG CGG CCT AAG GAT ATC TGC GAC GAT 373Pro Gly Pro Thr Val Arg Trp Lys Arg Pro Lys Asp Ile Cys Asp Asp45 50 55 60CCC CGG CTC TTC GTA GAT GGC ATC AGC TCC CAT GAC CTG CAC CAG GGC 421Pro Arg Leu Phe Val Asp Gly Ile Ser Ser His Asp Leu His Gln Gly
65 70 75CAG GTG GGC AAC TGC TGG TTT GTG GCT GCC TGC TCA TCA CTG GCC TCC 469Gln Val Gly Asn Cys Trp Phe Val Ala Ala Cys Ser Ser Leu Ala Ser
80 85 90CGA GAG TCA CTC TGG CAG AAG GTC ATC CCA GAC TGG AAG GAG CAG GAA 517Arg Glu Ser Leu Trp Gln Lys Val Ile Pro Asp Trp Lys Glu Gln Glu
95 100 105TGG AAC CCC GAG AAG CCT GAC AGC TAT GCT GGC ATC TTC CAC TTC AAC 565Trp Asn Pro Glu Lys Pro Asp Ser Tyr Ala Gly Ile Phe His Phe Asn
110 115 120TTC TGG CGC TTT GGG GAG TGG GTG GAC GTA ATC GTC GAT GAC CGG CTG 613Phe Trp Arg Phe Gly Glu Trp Val Asp Val Ile Val Asp Asp Arg Leu125 130 135 140CCC ACA GTC AAC AAC CAG CTC ATT TAC TGC CAT TCC AAC TCC AAA AAT 661Pro Thr Val Asn Asn Gln Leu Ile Tyr Cys His Ser Asn Ser Lys Asn
145 150 155GAG TTC TGG TGT GCC CTG GTG GAG AAG GCC TAT GCC AAG CTG GCC GGC 709Glu Phe Trp Cys Ala Leu Val Glu Lys Ala Tyr Ala Lys Leu Ala Gly
160 165 170TGT TAC CAG GCC CTG GAC GGA GGC AAC ACG GCC GAT GCA TTG GTG GAT 757Cys Tyr Gln Ala Leu Asp Gly Gly Asn Thr Ala Asp Ala Leu Val Asp
175 180 185TTC ACA GGT GGT GTT TCT GAA CCC ATT GAC CTG ACC GAG GGG GAC TTG 805Phe Thr Gly Gly Val Ser Glu Pro Ile Asp Leu Thr Glu Gly Asp Leu
190 195 200GCC ACT GAC GAG GCT AAG AGG AAT CAG CTC TTT GAG CGA GTG CTG AAG 853Ala Thr Asp Glu Ala Lys Arg Asn Gln Leu Phe Glu Arg Val Leu Lys205 210 215 220GTG CAC AGC AGA GGC GGG CTC ATC AGT GCC TCC ATC AAG GCT GTG ACA 901Val His Ser Arg Gly Gly Leu Ile Ser Ala Ser Ile Lys Ala Val Thr
225 230 235GCA GCT GAC ATG GAG GCC CGC CTG GCA TGT GGC CTG GTG AAG GGC CAT 949Ala Ala Asp Met Glu Ala Arg Leu Ala Cys Gly Leu Val Lys Gly His
240 245 250GCA TAC GCT GTC ACC GAT GTG CGC AAG GTG CGC CTG GGC CAT GGC CTG 997Ala Tyr Ala Val Thr Asp Val Arg Lys Val Arg Leu Gly His Gly Leu
255 260 265CTG GCC TTC TTC AAG TCA GAG AAG CTT GAT ATG ATC CGT CTG AGG AAC 1045Leu Ala Phe Phe Lys Ser Glu Lys Leu Asp Met Ile Arg Leu Arg Asn
270 275 280CCC TGG GGC GAG CGG GAG TGG ACG GGG CCC TGG AGT GAC ACG TCA GAG 1093Pro Trp Gly Glu Arg Glu Trp Thr Gly Pro Trp Ser Asp Thr Ser Glu285 290 295 300GAA TGG CAG AAA GTG AGC AAG AGT GAG AGG GAG AAG ATG GGC GTG ACC 1141Glu Trp Gln Lys Val Ser Lys Ser Glu Arg Glu Lys Met Gly Val Thr
305 310 315GTG CAG GAT GAT GGG GAA TTC TGG ATG ACC TTT GAG GAC ATG TGC CGG 1189Val Gln Asp Asp Gly Glu Phe Trp Met Thr Phe Glu Asp Met Cys Arg
320 325 330TAC TTT ACT GAC ATC ATT AAA TGC CGC CTG ATT AAC ACG TCC TAC CTG 1237Tyr Phe Thr Asp Ile Ile Lys Cys Arg Leu Ile Asn Thr Ser Tyr Leu
335 340 345AGC ATC CAT AAG ACA TGG GAG GAG GCC CGG CTG CAT GGT GCC TGG ACG 1285Ser Ile His Lys Thr Trp Glu Glu Ala Arg Leu His Gly Ala Trp Thr
350 355 360AGA CAT GAG GAC CCA CAG CAG AAC CGC AGT GGA GGC TGC ATC AAC CAC 1333Arg His Glu Asp Pro Gln Gln Asn Arg Ser Gly Gly Cys Ile Asn His365 370 375 380AAG GAC ACT TTC TTC CAG AAC CCA CAG TAC GTA TTT GAA GTC AAG AAG 1381Lys Asp Thr Phe Phe Gln Asn Pro Gln Tyr Val Phe Glu Val Lys Lys
385 390 395CCA GAA GAT GAA GTG TTG ATC AGT ATC CAG CAG CGG CCG AAG CGC TCA 1429Pro Glu Asp Glu Val Leu Ile Ser Ile Gln Gln Arg Pro Lys Arg Ser
400 405 410ACT CGC CGG GAG GGC AAA GGC GAG AAT CTG GCC ATT GGC TTC GAC ATC 1477Thr Arg Arg Glu Gly Lys Gly Glu Asn Leu Ala Ile Gly Phe Asp Ile
415 420 425TAT AAG GTG GAA GAG AAC CGC CAA TAC CGT ATG CAC AGC CTA CAG CAT 1525Tyr Lys Val Glu Glu Asn Arg Gln Tyr Arg Met His Ser Leu Gln His
430 435 440AAG GCC GCC AGC TCC ATC TAC ATC AAT TCC CGC AGC GTT TTT TTG AGG 1573Lys Ala Ala Ser Ser Ile Tyr Ile Asn Ser Arg Ser Val Phe Leu Arg445 450 455 460ACA GAG CTG CCC GAG GGC CGC TAC GTT ATC ATC CCT ACC ACC TTT GAG 1621Thr Glu Leu Pro Glu Gly Arg Tyr Val Ile Ile Pro Thr Thr Phe Glu
465 470 475CCA GGC CAC ACT GGC GAG TTC CTG CTC CGA GTC TTC ACA GAT GTC CCC 1669Pro Gly His Thr Gly Glu Phe Leu Leu Arg Val Phe Thr Asp Val Pro
480 485 490TCC AAC TGC CGG GAA CTA CGC CTG GAT GAG CCC CCT CGG ACC TGT TGG 1717Ser Asn Cys Arg Glu Leu Arg Leu Asp Glu Pro Pro Arg Thr Cys Trp
495 500 505AGT TCC CTC TGT GGC TAC CCT CAG CAG GTG GCC CAG GTA CAT GTC CTG 1765Ser Ser Leu Cys Gly Tyr Pro Gln Gln Val Ala Gln Val His Val Leu
510 515 520GGG GCT GCT GGC CTC AAG GAC TCC CCA ACA GGA GCA AAC TCA TAT GTG 1813Gly Ala Ala Gly Leu Lys Asp Ser Pro Thr Gly Ala Asn Ser Tyr Val525 530 535 540ATC ATC AAG TGT GAG GGC GAA AAG GTT CGC TCA GCT GTG CAG AGA GGG 1861Ile Ile Lys Cys Glu Gly Glu Lys Val Arg Ser Ala Val Gln Arg Gly
545 550 555ACC TCG ACA CCA GAG TAC AAT GTA AAA GGC ATC TTC TAT CGC AAG AAG 1909Thr Ser Thr Pro Glu Tyr Asn Val Lys Gly Ile Phe Tyr Arg Lys Lys
560 565 570CTG GCT CAG CCT ATC ACC GTG CAG GTT TGG AAT CAC CGA GTC CTG AAG 1957Leu Ala Gln Pro Ile Thr Val Gln Val Trp Asn His Arg Val Leu Lys
575 580 585GAT GAA TTC CTG GGC CAG GTG CAC CTG AAG ACT GCC CCG GAT GAC CTG 2005Asp Glu Phe Leu Gly Gln Val His Leu Lys Thr Ala Pro Asp Asp Leu
590 595 600CAG GAC CTC CAC ACC CTC CAT CTC CAG GAC CGC AGT AGC CGG CAG CCC 2053Gln Asp Leu His Thr Leu His Leu Gln Asp Arg Ser Ser Arg Gln Pro605 610 615 620AGT GAC CTG CCA GGC ATT GTA GCT GTG CGA GTC CTC TGC AGT GCC TCT 2101Ser Asp Leu Pro Gly Ile Val Ala Val Arg Val Leu Cys Ser Ala Ser
625 630 635CTC ACG GCT GTC TGACCCCAGC CTGCCTGTCC TGCCCCACTA GTCCTCACCA 2153Leu Thr Ala Val
640CTACTCGCAT GTCCCCACCT TGCCTGGGAC CAGCCTGGGA ACCAGACACT GGGGCCCTTT 2213CCTCACTCTT CCACTGACCC ACTGTGTGAC CTGAAGAGAG CCCTGCCCTC TCTGAGCCTC 2273AGTGTTTGGA GGGCCCCAAA GAATTCCCGT CTTGTGGGGG AGTTTTCTTG CCTAAGATTT 2333AATGCAGTTC TCTCTACCCA GTGGGCGCTG CTGTTAAGGG GCCATCTGCT GAAAACGTTT 2393CCCCAGGCCC TGCTGTCTGC CAGGAGTGCC AAGTGTCAAC TGTTTACACA CAAACTGCCA 2453TGTCCC 2459(2)序列2资料:(i)序列特征:
(A)长度:640个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线形(ii)分子类型:蛋白(xi)序列描述:序列2:Met Phe Ser Cys Ala Lys Ala Tyr Glu Asp Gln Asn Tyr Ser Ala Leu1 5 10 15Lys Arg Ala Cys Leu Arg Lys Lys Val Leu Phe Glu Asp Pro Leu Phe
20 25 30Pro Ala Thr Asp Asp Ser Leu Tyr Tyr Lys Gly Thr Pro Gly Pro Thr
35 40 45Val Arg Trp Lys Arg Pro Lys Asp Ile Cys Asp Asp pro Arg Leu phe
50 55 60Val Asp Gly Ile Ser Ser His Asp Leu His Gln Gly Gln Val Gly Asn65 70 75 80Cys Trp Phe Val Ala Ala Cys Ser Ser Leu Ala Ser Arg Glu Ser Leu
85 90 95Trp Gln Lys Val Ile Pro Asp Trp Lys Glu Gln Glu Trp Asn Pro Glu
100 105 110Lys Pro Asp Ser Tyr Ala Gly Ile Phe His Phe Asn Phe Trp Arg Phe
115 120 125Gly Glu Trp Val Asp Val Ile Val Asp Asp Arg Leu Pro Thr Val Asn
130 135 140Asn Gln Leu Ile Tyr Cys His Ser Asn Ser Lys Asn Glu Phe Trp Cys145 150 155 160Ala Leu Val Glu Lys Ala Tyr Ala Lys Leu Ala Gly Cys Tyr Gln Ala
165 170 175Leu Asp Gly Gly Asn Thr Ala Asp Ala Leu Val Asp Phe Thr Gly Gly
180 185 190Val Ser Glu Pro Ile Asp Leu Thr Glu Gly Asp Leu Ala Thr Asp Glu
195 200 205Ala Lys Arg Asn Gln Leu Phe Glu Arg Val Leu Lys Val His Ser Arg
210 215 220Gly Gly Leu Ile Ser Ala Ser Ile Lys Ala Val Thr Ala Ala Asp Met225 230 235 240Glu Ala Arg Leu Ala Cys Gly Leu Val Lys Gly His Ala Tyr Ala Val
245 250 255Thr Asp Val Arg Lys Val Arg Leu Gly His Gly Leu Leu Ala Phe Phe
260 265 270Lys Ser Glu Lys Leu Asp Met Ile Arg Leu Arg Asn Pro Trp Gly Glu
275 280 285Arg Glu Trp Thr Gly Pro Trp Ser Asp Thr Ser Glu Glu Trp Gln Lys
290 295 300Val Ser Lys Ser Glu Arg Glu Lys Met Gly Val Thr Val Gln Asp Asp305 310 315 320Gly Glu Phe Trp Met Thr Phe Glu Asp Met Cys Arg Tyr Phe Thr Asp
325 330 335Ile Ile Lys Cys Arg Leu Ile Asn Thr Ser Tyr Leu Ser Ile His Lys
340 345 350Thr Trp Glu Glu Ala Arg Leu His Gly Ala Trp Thr Arg His Glu Asp
355 360 365Pro Gln Gln Asn Arg Ser Gly Gly Cys Ile Asn His Lys Asp Thr Phe
370 375 380Phe Gln Asn Pro Gln Tyr Val Phe Glu Val Lys Lys Pro Glu Asp Glu385 390 395 400Val Leu Ile Ser Ile Gln Gln Arg Pro Lys Arg Ser Thr Arg Arg Glu
405 410 415Gly Lys Gly Glu Asn Leu Ala Ile Gly Phe Asp Ile Tyr Lys Val Glu
420 425 430Glu Asn Arg Gln Tyr Arg Met His Ser Leu Gln His Lys Ala Ala Ser
435 440 445Ser Ile Tyr Ile Asn Ser Arg Ser Val Phe Leu Arg Thr Glu Leu Pro
450 455 460Glu Gly Arg Tyr Val Ile Ile Pro Thr Thr Phe Glu Pro Gly His Thr465 470 475 480Gly Glu Phe Leu Leu Arg Val Phe Thr Asp Val Pro Ser Asn Cys Arg
485 490 495Glu Leu Arg Leu Asp Glu Pro Pro Arg Thr Cys Trp Ser Ser Leu Cys
500 505 510Gly Tyr Pro Gln Gln Val Ala Gln Val His Val Leu Gly Ala Ala Gly
515 520 525Leu Lys Asp Ser Pro Thr Gly Ala Asn Ser Tyr Val Ile Ile Lys Cys
530 535 540Glu Gly Glu Lys Val Arg Ser Ala Val Gln Arg Gly Thr Ser Thr Pro545 550 555 560Glu Tyr Asn Val Lys Gly Ile Phe Tyr Arg Lys Lys Leu Ala Gln Pro
565 570 575Ile Thr Val Gln Val Trp Asn His Arg Val Leu Lys Asp Glu Phe Leu
580 585 590Gly Gln Val His Leu Lys Thr Ala Pro Asp Asp Leu Gln Asp Leu His
595 600 605Thr Leu His Leu Gln Asp Arg Ser Ser Arg Gln Pro Ser Asp Leu Pro
610 615 620Gly Ile Val Ala Val Arg Val Leu Cys Ser Ala Ser Leu Thr Ala Val625 630 635 640(2)序列3资料:(i)序列特征:
(A)长度:1743个碱基对
(B)类型:核酸
(C)链型:单
(D)拓扑结构:线形(ii)分子类型:cDNA(iii)假说:无(iii)反义:无(vi)来源:
(A)生物:小家鼠(Mus musculus)
(B)品系:balb/c(ix)特征
(A)名称/键:5’UTR
(B)位置:1..193(ix)特征
(A)名称/键:3’UTR
(B)位置:1736..1743(ix)特征
(A)名称/键:CDS
(B)位置:194..1735(xi)序列描述:序列3:CTGAAGCCCG GGGGTCCAAG TTCCAACCCC CGCCTGCGGG CTGCCGGGGT ATCATCTCCC 60CGCAGAGTCC CGGCCGTGGC GCGGGCTGGT CTAGCCTCCG CTCCAGTGCC CGCACTGTGC 120TCTGCATCCC GGGAGTCCAG CTCCAGCTGC GGCGACGCGG CAGGTGCCTC CCCTTCTTGG 180GGACGTGGTC ACC ATG TTC TCC TGC GCG AAG GCC TAT GAG GAC CAG AAC 229
Met Phe Ser Cys Ala Lys Ala Tyr Glu Asp Gln Asn
1 5 10TAC TCG GCG CTG AAG CGG GCC TGC CTG CGC AAG AAG GTG CTG TTC GAG 277Tyr Ser Ala Leu Lys Arg Ala Cys Leu Arg Lys Lys Val Leu Phe Glu
15 20 25GAT CCC CTC TTC CCT GCC ACC GAC GAC TCC CTT TAC TAT AAG GGC ACC 325Asp Pro Leu Phe Pro Ala Thr Asp Asp Ser Leu Tyr Tyr Lys Gly Thr
30 35 40CCA GGG CCC ACA GTC AGG TGG AAG CGG CCT AAG GAT ATC TGC GAC GAT 373Pro Gly Pro Thr Val Arg Trp Lys Arg Pro Lys Asp Ile Cys Asp Asp45 50 55 60CCC CGG CTC TTC GTA GAT GGC ATC AGC TCC CAT GAC CTG CAC CAG GGC 421Pro Arg Leu Phe Val Asp Gly Ile Ser Ser His Asp Leu His Gln Gly
65 70 75CAG GTG GGC AAC TGC TGG TTT GTG GCT GCC TGC TCA TCA CTG GCC TCC 469Gln Val Gly Asn Cys Trp Phe Val Ala Ala Cys Ser Ser Leu Ala Ser
80 85 90CGA GAG TCA CTC TGG CAG AAG GTC ATC CCA GAC TGG AAG GAG CAG GAA 517Arg Glu Ser Leu Trp Gln Lys Val Ile Pro Asp Trp Lys Glu Gln Glu
95 100 l05TGG AAC CCC GAG AAG CCT GAC AGC TAT GCT GGC ATC TTC CAC TTC AAC 565Trp Asn Pro Glu Lys Pro Asp Ser Tyr Ala Gly Ile Phe His Phe Asn
110 115 120TTC TGG CGC TTT GGG GAG TGG GTG GAC GTA ATC GTC GAT GAC CGG CTG 613Phe Trp Arg Phe Gly Glu Trp Val Asp Val Ile Val Asp Asp Arg Leu125 130 135 140CCC ACA GTC AAC AAC CAG CTC ATT TAC TGC CAT TCC AAC TCC AAA AAT 661Pro Thr Val Asn Asn Gln Leu Ile Tyr Cys His Ser Asn Ser Lys Asn
145 150 155GAG TTC TGG TGT GCC CTG GTG GAG AAG GCC TAT GCC AAG CTG GCC GGC 709Glu Phe Trp Cys Ala Leu Val Glu Lys Ala Tyr Ala Lys Leu Ala Gly
160 165 170TGT TAC CAG GCC CTG GAC GGA GGC AAC ACG GCC GAT GCA TTG GTG GAT 757Cys Tyr Gln Ala Leu Asp Gly Gly Asn Thr Ala Asp Ala Leu Val Asp
175 180 185TTC ACA GGT GGT GTT TCT GAA CCC ATT GAC CTG ACC GAG GGG GAC TTG 805Phe Thr Gly Gly Val Ser Glu Pro Ile Asp Leu Thr Glu Gly Asp Leu
190 195 200GCC ACT GAC GAG GCT AAG AGG AAT CAG CTC TTT GAG CGA GTG CTG AAG 853Ala Thr Asp Glu Ala Lys Arg Asn Gln Leu Phe Glu Arg Val Leu Lys205 210 215 220GTG CAC AGC AGA GGC GGG CTC ATC AGT GCC TCC ATC AAG GCT GTG ACA 901Val His Ser Arg Gly Gly Leu Ile Ser Ala Ser Ile Lys Ala Val Thr
225 230 235GCA GCT GAC ATG GAG GCC CGC CTG GCA TGT GGC CTG GTG AAG GGC CAT 949Ala Ala Asp Met Glu Ala Arg Leu Ala Cys Gly Leu Val Lys Gly His
240 245 250GCA TAC GCT GTC ACC GAT GTG CGC AAG GTG CGC CTG GGC CAT GGC CTG 997Ala Tyr Ala Val Thr Asp Val Arg Lys Val Arg Leu Gly His Gly Leu
255 260 265CTG GCC TTC TTC AAG TCA GAG AAG CTT GAT ATG ATC CGT CTG AGG AAC 1045Leu Ala Phe Phe Lys Ser Glu Lys Leu Asp Met Ile Arg Leu Arg Asn
270 275 280CCC TGG GGC GAG CGG GAG TGG ACGGGG CCC TGG AGT GAC ACG TCA GAG 1093Pro Trp Gly Glu Arg Glu Trp Thr Gly Pro Trp Ser Asp Thr Ser Glu285 290 295 300GAA TGG CAG AAA GTG AGC AAG AGT GAG AGG GAG AAG ATG GGC GTG ACC 1141Glu Trp Gln Lys Val Ser Lys Ser Glu Arg Glu Lys Met Gly Val Thr
305 310 315GTG CAG GAT GAT GGG GAA TTC TGG ATG ACC TTT GAG GAC ATG TGC CGG 1189Val Gln Asp Asp Gly Glu Phe Trp Met Thr Phe Glu Asp Met Cys Arg
320 325 330TAC TTT ACT GAC ATC ATT AAA TGC CGC CTG ATT AAC ACG TCC TAC CTG 1237Tyr Phe Thr Asp Ile Ile Lys Cys Arg Leu Ile Asn Thr Ser Tyr Leu
335 340 345AGC ATC CAT AAG ACA TGG GAG GAG GCC CGG CTG CAT GGT GCC TGG ACG 1285Ser Ile His Lys Thr Trp Glu Glu Ala Arg Leu His Gly Ala Trp Thr
350 355 360AGA CAT GAG GAC CCA CAG CAG AAC CGC AGT GGA GGC TGC ATC AAC CAC 1333Arg His Glu Asp Pro Gln Gln Asn Arg Ser Gly Gly Cys Ile Asn His365 370 375 380AAG GAC ACT TTC TTC CAG AAC CCA CAG TAC GTA TTT GAA GTC AAG AAG 1381Lys Asp Thr Phe Phe Gln Asn Pro Gln Tyr Val Phe Glu Val Lys Lys
385 390 395CCA GAA GAT GAA GTG TTG ATC AGT ATC CAG CAG CGG CCG AAG CGC TCA 1429Pro Glu Asp Glu Val Leu Ile Ser Ile Gln Gln Arg Pro Lys Arg Ser
400 405 410ACT CGC CGG GAG GGC AAA GGC GAG AAT CTG GCC ATT GGC TTC GAC ATC 1477Thr Arg Arg Glu Gly Lys Gly Glu Asn Leu Ala Ile Gly Phe Asp Ile
415 420 425TAT AAG GTG GAA GAG AAC CGC CAA TAC CGT ATG CAC AGC CTA CAG CAT 1525Tyr Lys Val Glu Glu Asn Arg Gln Tyr Arg Met His Ser Leu Gln His
430 435 440AAG GCC GCC AGC TCC ATC TAC ATC AAT TCC CGC AGC GTT TTT TTG AGG 1573Lys Ala Ala Ser Ser Ile Tyr Ile Asn Ser Arg Ser Val Phe Leu Arg445 450 455 460ACA GAG CTG CCC GAG GGC CGC TAC GTT ATC ATC CCT ACC ACC TTT GAG 1621Thr Glu Leu Pro Glu Gly Arg Tyr Val Ile Ile Pro Thr Thr Phe Glu
465 470 475CCA GGC CAC ACT GGC GAG TTC CTG CTC CGA GTC TTC ACA GAT GTC CCC 1669Pro Gly His Thr Gly Glu Phe Leu Leu Arg Val Phe Thr Asp Val Pro
480 485 490TCC AAC TGC CGG TGT GTG GGG GCT AGG GCT AGT GAC CGC ATG CAT ATA 1717Ser Asn Cys Arg Cys Val Gly Ala Arg Ala Ser Asp Arg Met His Ile
495 500 505TAC CCC ATG CTG GGC TAGATTTTAA C 1743Tyr Pro Met Leu Gly
510(2)序列4资料:(i)序列特征:
(A)长度:513个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线形(ii)分子类型:蛋白(xi)序列描述:序列4:Met Phe Ser Cys Ala Lys Ala Tyr Glu Asp Gln Asn Tyr Ser Ala Leu1 5 10 15Lys Arg Ala Cys Leu Arg Lys Lys Val Leu Phe Glu Asp Pro Leu Phe
20 25 30Pro Ala Thr Asp Asp Ser Leu Tyr Tyr Lys Gly Thr Pro Gly Pro Thr
35 40 45Val Arg Trp Lys Arg Pro Lys Asp Ile Cys Asp Asp Pro Arg Leu Phe
50 55 60Val Asp Gly Ile Ser Ser His Asp Leu His Gln Gly Gln Val Gly Asn65 70 75 80Cys Trp Phe Val Ala Ala Cys Ser Ser Leu Ala Ser Arg Glu Ser Leu
85 90 95Trp Gln Lys Val Ile Pro Asp Trp Lys Glu Gln Glu Trp Asn Pro Glu
100 105 110Lys Pro Asp Ser Tyr Ala Gly Ile Phe His Phe Asn Phe Trp Arg Phe
115 120 125Gly Glu Trp Val Asp Val Ile Val Asp Asp Arg Leu Pro Thr Val Asn
130 135 140Asn Gln Leu Ile Tyr Cys His Ser Asn Ser Lys Asn Glu Phe Trp Cys145 150 155 160Ala Leu Val Glu Lys Ala Tyr Ala Lys Leu Ala Gly Cys Tyr Gln Ala
165 170 175Leu Asp Gly Gly Asn Thr Ala Asp Ala Leu Val Asp Phe Thr Gly Gly
180 185 190Val Ser Glu Pro Ile Asp Leu Thr Glu Gly Asp Leu Ala Thr Asp Glu
195 200 205Ala Lys Arg Asn Gln Leu Phe Glu Arg Val Leu Lys Val His Ser Arg
210 215 220Gly Gly Leu Ile Ser Ala Ser Ile Lys Ala Val Thr Ala Ala Asp Met225 230 235 240Glu Ala Arg Leu Ala Cys Gly Leu Val Lys Gly His Ala Tyr Ala Val
245 250 255Thr Asp Val Arg Lys Val Arg Leu Gly His Gly Leu Leu Ala Phe Phe
260 265 270Lys Ser Glu Lys Leu Asp Met Ile Arg Leu Arg Asn Pro Trp Gly Glu
275 280 285Arg Glu Trp Thr Gly Pro Trp Ser Asp Thr Ser Glu Glu Trp Gln Lys
290 295 300Val Ser Lys Ser Glu Arg Glu Lys Met Gly Val Thr Val Gln Asp Asp305 310 315 320Gly Glu Phe Trp Met Thr Phe Glu Asp Met Cys Arg Tyr Phe Thr Asp
325 330 335Ile Ile Lys Cys Arg Leu Ile Asn Thr Ser Tyr Leu Ser Ile His Lys
340 345 350Thr Trp Glu Glu Ala Arg Leu His Gly Ala Trp Thr Arg His Glu Asp
355 360 365Pro Gln Gln Asn Arg Ser Gly Gly Cys Ile Asn His Lys Asp Thr Phe
370 375 380Phe Gln Asn Pro Gln Tyr Val Phe Glu Val Lys Lys Pro Glu Asp Glu385 390 395 400Val Leu Ile Ser Ile Gln Gln Arg Pro Lys Arg Ser Thr Arg Arg Glu
405 410 415Gly Lys Gly Glu Asn Leu Ala Ile Gly Phe Asp Ile Tyr Lys Val Glu
420 425 430Glu Asn Arg Gln Tyr Arg Met His Ser Leu Gln His Lys Ala Ala Ser
435 440 445Ser Ile Tyr Ile Asn Ser Arg Ser Val Phe Leu Arg Thr Glu Leu Pro
450 455 460Glu Gly Arg Tyr Val Ile Ile Pro Thr Thr Phe Glu Pro Gly His Thr465 470 475 480Gly Glu Phe Leu Leu Arg Val Phe Thr Asp Val Pro Ser Asn Cys Arg
485 490 495Cys Val Gly Ala Arg Ala Ser Asp Arg Met His Ile Tyr Pro Met Leu
500 505 510Gly(2)序列5资料:(i)序列特征:
(A)长度:504个碱基对
(B)类型:核酸
(C)链型:单
(D)拓扑结构:线形 (ii)分子类型:DNA(基因组)(iii)假说:无(iii)反义:无(vi)来源:
(A)生物:小家鼠(Mus musculus)
(B)品系:ES E14(vii)直接来源:
(B)克隆:29/30(ix)特征
(A)名称/键:外显子
(B)位置:1..33(ix)特征
(A)名称/键:内含子
(B)位置:34..440(ix)特征
(A)名称/键:外显子
(B)位置:441..504(xi)序列描述:序列5:CGAGCGGGAG TGGACGGGCC CCTGGAGTGA CACGTGAGGC TCACCAGGGT TGGGGCTGGG 60TATGGGCACA GAGGCAAGGA CAAGCGGTGA CACTGGACTG GGCCTTGCAG GGTCTGGGAG 120AGATGCTCTG AGGAAAAAAT GGGAGACTTA CTTTCCAGTG TAAGTGTGGT GCTTGGGGGG 180TAGGTTCATC AAGGACAGTG GCCAGAAGTG TGGCATGCTT TGTACGTGGA CAATGGCGCC 240TCACCAGCTT TATTCCCTGA CTTCATAGCC TTAGCATAAA GGAAGATCAC AGTTCCTAGT 300GGGAGAGAAC AGAGGCTTCT TAGCAGGGCT GGGCATGGCC TCCAGGTCTC TACCCACAGT 360GCTCTGCAGG CGGCTTGGTC CAGAGCTCTC CCTTGGGCCA CTCCTCTTAT CCCGTTCCCT 420CCCTGATACT CACTCCCCAG GTCAGAGGAA TGGCAGAAAG TGAGCAAGAG TGAGAGGGAG 480AAGATGGGCG TGACCGTGCA GGAT 504(2)序列6资料:(i)序列特征:
(A)长度:1975个碱基对
(B)类型:核酸
(C)链型:单
(D)拓扑结构:线形(ii)分子类型:cDNA(iii)假说:无(iii)反义:无(vi)来源:
(A)生物:人类(Homo sapiens)(vii)直接来源:
(B)克隆:nCL-3(ix)特征
(A)名称/键:5’UTR
(B)位置:1..43(ix)特征
(A)名称/键:3’UTR
(B)位置:1964..1975(ix)特征
(A)名称/键:CDS
(B)位置:44..1963(xi)序列描述:序列6:ACTCACTATA GGGCTCGAGC GGCCGCCCGG GCAGGTAGCC ACC ATG TTC TCG TGT 55
Met Phe Ser Cys
1GTG AAG CCC TAT GAG GAC CAG AAC TAC TCA GCC CTG AGG CGG GAC TGC 103Val Lys Pro Tyr Glu Asp Gln Asn Tyr Ser Ala Leu Arg Arg Asp Cys5 10 15 20CGG CGC AGG AAG GTG CTC TTC GAG GAC CCC CTC TTC CCC GCC ACT GAC 151Arg Arg Arg Lys Val Leu Phe Glu Asp Pro Leu Phe Pro Ala Thr Asp
25 30 35GAC TCA CTC TAC TAT AAG GGC ACG CCG GGG CCC GCC GTC AGG CGG AAG 199Asp Ser Leu Tyr Tyr Lys Gly Thr Pro Gly Pro Ala Val Arg Arg Lys
40 45 50CGA CCC AAG GGC ATC TGC GAG GAC CCC CGC CTC TTT GTG GAT GGC ATC 247Arg Pro Lys Gly Ile Cys Glu Asp Pro Arg Leu Phe Val Asp Gly Ile
55 60 65AGC TCC CAC GAC CTG CAC CAG GGC CAG GTG GGC AAC TGC TGG TTT GTG 295Ser Ser His Asp Leu His Gln Gly Gln Val Gly Asn Cys Trp Phe Val
70 75 80GCA GCC TGC TCG TCA CTT GCC TCC CGG GAG TCG CTG TGG CAA AAG GTC 343Ala Ala Cys Ser Ser Leu Ala Ser Arg Glu Ser Leu Trp Gln Lys Val
85 90 95 100ATC CCA GAC TGG AAG GAG CAG GAA TGG GAC CCC GAA AAG CCC AAC GCC 391Ile Pro Asp Trp Lys Glu Gln Glu Trp Asp Pro Glu Lys Pro Asn Ala
105 110 115TAC GCG GGC ATC TTC CAC TTC CAC TTC TGG CGC TTC GGG GAA TGG GTG 439Tyr Ala Gly Ile Phe His Phe His Phe Trp Arg Phe Gly Glu Trp Val
120 125 130GAC GTG GTC ATC GAT GAC CGG CTG CCC ACA GTC AAC AAC CAG CTC ATC 487Asp Val Val Ile Asp Asp Arg Leu Pro Thr Val Asn Asn Gln Leu Ile
135 140 145TAC TGC CAC TCC AAC TCC CGC AAT GAG TTT TGG TGC GCC CTA GTG GAG 535Tyr Cys His Ser Asn Ser Arg Asn Glu Phe Trp Cys Ala Leu Val Glu
150 155 160AAG GCC TAT GCC AAA CTG GCA GGC TGT TAC CAG GCC CTG GAT GGA GGC 583Lys Ala Tyr Ala Lys Leu Ala Gly Cys Tyr Gln Ala Leu Asp Gly Gly165 170 175 180AAC ACA GCA GAC GCA CTG GTG GAC TTC ACG GGT GGT GTT TCT GAG CCC 631Asn Thr Ala Asp Ala Leu Val Asp Phe Thr Gly Gly Val Ser Glu Pro
185 190 195ATC GAC CTG ACC GAG GGT GAC TTT GCC AAC GAT GAG ACT AAG AGG AAC 679Ile Asp Leu Thr Glu Gly Asp Phe Ala Asn Asp Glu Thr Lys Arg Asn
200 205 210CAG CTC TTT GAG CGC ATG TTA AAG GTG CAC AGC CGG GGC GGC CTC ATC 727Gln Leu Phe Glu Arg Met Leu Lys Val His Ser Arg Gly Gly Leu Ile
215 220 225AGT GCC TCC ATC AAG GCA GTG ACA GCA GCT GAC ATG GAG GCC CGC CTG 775Ser Ala Ser Ile Lys Ala Val Thr Ala Ala Asp Met Glu Ala Arg Leu
230 235 240GCG TGC GGC CTG GTA AAG GGC CACGCA TAC GCC GTC ACT GAT GTG CGC 823Ala Cys Gly Leu Val Lys Gly His Ala Tyr Ala Val Thr Asp Val Arg245 250 255 260AAG GTG CGC CTG GGC CAC GGC CTA CTG GCC TTC TTC AAG TCA GAG AAG 871Lys Val Arg Leu Gly His Gly Leu Leu Ala Phe Phe Lys Ser Glu Lys
265 270 275TTG GAC ATG ATC CGC CTG CGC AAC CCC TGG GGC GAG CGG GAG TGG AAC 919Leu Asp Met Ile Arg Leu Arg Asn Pro Trp Gly Glu Arg Glu Trp Asn
280 285 290GGG CCC TGG AGT GAC ACC TCG GAG GAG TGG CAG AAA GTG AGC AAG AGT 967Gly Pro Trp Ser Asp Thr Ser Glu Glu Trp Gln Lys Val Ser Lys Ser
295 300 305GAG CGG GAG AAG ATG GGT GTG ACC GTG CAG GAC GAC GGT GAG TTC TGG 1015Glu Arg Glu Lys Met Gly Val Thr Val Gln Asp Asp Gly Glu Phe Trp
310 315 320ATG ACC TTC GAG GAC GTG TGC CGG TAC TTC ACG GAC ATC ATC AAG TGC 1063Met Thr Phe Glu Asp Val Cys Arg Tyr Phe Thr Asp Ile Ile Lys Cys325 330 335 340CGC GTG ATC AAC ACA TCC CAC CTG AGC ATC CAC AAG ACG TGG GAG GAG 1111Arg Val Ile Asn Thr Ser His Leu Ser Ile His Lys Thr Trp Glu Glu
345 350 355GCC CGG CTG CAT GGC GCC TGG ACG CTG CAT GAG GAC CCG CGA CAG AAC 1159Ala Arg Leu His Gly Ala Trp Thr Leu His Glu Asp Pro Arg Gln Asn
360 365 370CGC GGT GGC GGC TGC ATC AAC CAC AAG GAC ACC TTC TTC CAG AAC CCA 1207Arg Gly Gly Gly Cys Ile Asn His Lys Asp Thr Phe Phe Gln Asn Pro
375 380 385CAG TAC ATC TTC GAA GTC AAG AAG CCA GAA GAT GAA GTC CTG ATC TGT 1255Gln Tyr Ile Phe Glu Val Lys Lys Pro Glu Asp Glu Val Leu Ile Cys
390 395 400ATC CAG CAG CGG CCA AAG CGG TCT ACG CGC CGG GAG GGC AAG GGT GAG 1303Ile Gln Gln Arg Pro Lys Arg Ser Thr Arg Arg Glu Gly Lys Gly Glu405 410 415 420AAC CTG GCC ATT GGC TTT GAC ATC TAC AAG GTG GAG GAG AAC CGC CAG 1351Asn Leu Ala Ile Gly Phe Asp Ile Tyr Lys Val Glu Glu Asn Arg Gln
425 430 435TAC CGC ATG CAC AGC CTG CAG CAC AAG GCC GCC AGC TCC ATC TAC ATC 1399Tyr Arg Met His Ser Leu Gln His Lys Ala Ala Ser Ser Ile Tyr Ile
440 445 450AAC TCA CGC AGC GTC TTC CTG CGC ACC GAC CAG CCC GAG GGC CGC TAT 1447Asn Ser Arg Ser Val Phe Leu Arg Thr Asp Gln Pro Glu Gly Arg Tyr
455 460 465GTC ATC ATC CCC ACA ACC TTC GAG CCA GGC CAC ACT GGC GAG TTC CTG 1495Val Ile Ile Pro Thr Thr Phe Glu Pro Gly His Thr Gly Glu Phe Leu
470 475 480CTC CGA GTC TTC ACT GAT GTG CCC TCC AAC TGC CGG GAG CTG CGC CTG 1543Leu Arg Val Phe Thr Asp Val Pro Ser Asn Cys Arg Glu Leu Arg Leu485 490 495 500GAT GAG CCC CCA CAC ACC TGC TGG AGC TCC CTC TGT GGC TAC CCC CAG 1591Asp Glu Pro Pro His Thr Cys Trp Ser Ser Leu Cys Gly Tyr Pro Gln
505 510 515CTG GTG ACC CAG GTA CAT GTC CTG GGA GCT GCT GGC CTC AAG GAC TCC 1639Leu Val Thr Gln Val His Val Leu Gly Ala Ala Gly Leu Lys Asp Ser
520 525 530CCA ACA GGG GCT AAC TCT TAT GTG ATC ATC AAG TGT GAG GGA GAC AAA 1687Pro Thr Gly Ala Asn Ser Tyr Val Ile Ile Lys Cys Glu Gly Asp Lys
535 540 545GTC CGC TCG GCT GTG CAG AAG GGC ACC TCC ACA CCA GAG TAC AAT GTG 1735Val Arg Ser Ala Val Gln Lys Gly Thr Ser Thr Pro Glu Tyr Asn Val
550 555 560AAA GGC ATC TTC TAC CGC AAG AAG CTG AGC CAG CCC ATC ACT GTA CAG 1783Lys Gly Ile Phe Tyr Arg Lys Lys Leu Ser Gln Pro Ile Thr Val Gln565 570 575 580GTC TGG AAC CAC CGA GTG CTG AAG GAT GAA TTT CTG GGC CAG GTG CAC 1831Val Trp Asn His Arg Val Leu Lys Asp Glu Phe Leu Gly Gln Val His
585 590 595CTA AAG GCT GAC CCG GAC AAC CTC CAG GCC CTG CAT ACC CTC CAC CTC 1879Leu Lys Ala Asp Pro Asp Asn Leu Gln Ala Leu His Thr Leu His Leu
600 605 610CGG GAC CGA AAT AGC CGG CAG CCC AGC AAC CTG CCA GGC ACT GTG GCC 1927Arg Asp Arg Asn Ser Arg Gln Pro Ser Asn Leu Pro Gly Thr Val Ala
615 620 625GTG CAC ATT CTC AGC AGC ACC TCT CTC ACG GCT GTC TGACTCGAGC 1973Val His Ile Leu Ser Ser Thr Ser Leu Thr Ala Val
630 635 640TA 1975(2)序列7资料:(i)序列特征:
(A)长度:640个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线形(ii)分子类型:蛋白(xi)序列描述:序列7:Met Phe Ser Cys Val Lys Pro Tyr Glu Asp Gln Asn Tyr Ser Ala Leu1 5 10 15Arg Arg Asp Cys Arg Arg Arg Lys Val Leu Phe Glu Asp Pro Leu Phe
20 25 30Pro Ala Thr Asp Asp Ser Leu Tyr Tyr Lys Gly Thr Pro Gly Pro Ala
35 40 45Val Arg Arg Lys Arg Pro Lys Gly Ile Cys Glu Asp Pro Arg Leu Phe
50 55 60Val Asp Gly Ile Ser Ser His Asp Leu His Gln Gly Gln Val Gly Asn65 70 75 80Cys Trp Phe Val Ala Ala Cys Ser Ser Leu Ala Ser Arg Glu Ser Leu
85 90 95Trp Gln Lys Val Ile Pro Asp Trp Lys Glu Gln Glu Trp Asp Pro Glu
100 105 110Lys Pro Asn Ala Tyr Ala Gly Ile Phe His Phe His Phe Trp Arg Phe
115 120 125Gly Glu Trp Val Asp Val Val Ile Asp Asp Arg Leu Pro Thr Val Asn
130 135 140Asn Gln Leu Ile Tyr Cys His Ser Asn Ser Arg Asn Glu Phe Trp Cys145 150 155 160Ala Leu Val Glu Lys Ala Tyr Ala Lys Leu Ala Gly Cys Tyr Gln Ala
165 170 175Leu Asp Gly Gly Asn Thr Ala Asp Ala Leu Val Asp Phe Thr Gly Gly
180 185 190Val Ser Glu Pro Ile Asp Leu Thr Glu Gly Asp Phe Ala Asn Asp Glu
195 200 205Thr Lys Arg Asn Gln Leu Phe Glu Arg Met Leu Lys Val His Ser Arg
210 215 220Gly Gly Leu Ile Ser Ala Ser Ile Lys Ala Val Thr Ala Ala Asp Met225 230 235 240Glu Ala Arg Leu Ala Cys Gly Leu Val Lys Gly His Ala Tyr Ala Val
245 250 255Thr Asp Val Arg Lys Val Arg Leu Gly His Gly Leu Leu Ala Phe Phe
260 265 270Lys Ser Glu Lys Leu Asp Met Ile Arg Leu Arg Asn Pro Trp Gly Glu
275 280 285Arg Glu Trp Asn Gly Pro Trp Ser Asp Thr Ser Glu Glu Trp Gln Lys
290 295 300Val Ser Lys Ser Glu Arg Glu Lys Met Gly Val Thr Val Gln Asp Asp305 310 315 320Gly Glu Phe Trp Met Thr Phe Glu Asp Val Cys Arg Tyr Phe Thr Asp
325 330 335Ile Ile Lys Cys Arg Val Ile Asn Thr Ser His Leu Ser Ile His Lys
340 345 350Thr Trp Glu Glu Ala Arg Leu His Gly Ala Trp Thr Leu His Glu Asp
355 360 365Pro Arg Gln Asn Arg Gly Gly Gly Cys Ile Asn His Lys Asp Thr Phe
370 375 380Phe Gln Asn Pro Gln Tyr Ile Phe Glu Val Lys Lys Pro Glu Asp Glu385 390 395 400Val Leu Ile Cys Ile Gln Gln Arg Pro Lys Arg Ser Thr Arg Arg Glu
405 410 415Gly Lys Gly Glu Asn Leu Ala Ile Gly Phe Asp Ile Tyr Lys Val Glu
420 425 430Glu Asn Arg Gln Tyr Arg Met His Ser Leu Gln His Lys Ala Ala Ser
435 440 445Ser Ile Tyr Ile Asn Ser Arg Ser Val Phe Leu Arg Thr Asp Gln Pro
450 455 460Glu Gly Arg Tyr Val Ile Ile Pro Thr Thr Phe Glu Pro Gly His Thr465 470 475 480Gly Glu Phe Leu Leu Arg Val Phe Thr Asp Val Pro Ser Asn Cys Arg
485 490 495Glu Leu Arg Leu Asp Glu Pro Pro His Thr Cys Trp Ser Ser Leu Cys
500 505 510Gly Tyr Pro Gln Leu Val Thr Gln Val His Val Leu Gly Ala Ala Gly
515 520 525Leu Lys Asp Ser Pro Thr Gly Ala Asn Ser Tyr Val Ile Ile Lys Cys
530 535 540Glu Gly Asp Lys Val Arg Ser Ala Val Gln Lys Gly Thr Ser Thr Pro545 550 555 560Glu Tyr Asn Val Lys Gly Ile Phe Tyr Arg Lys Lys Leu Ser Gln Pro
565 570 575Ile Thr Val Gln Val Trp Asn His Arg Val Leu Lys Asp Glu Phe Leu
580 585 590Gly Gln Val His Leu Lys Ala Asp Pro Asp Asn Leu Gln Ala Leu His
595 600 605Thr Leu His Leu Arg Asp Arg Asn Ser Arg Gln Pro Ser Asn Leu Pro
610 615 620Gly Thr Val Ala Val His Ile Leu Ser Ser Thr Ser Leu Thr Ala Val625 630 635 640
Claims (20)
1.一种具有序列1的序列的nCL-3钙蛋白酶基因或其等位变体,类似物或衍生物,所述等位变体在衍生的氨基酸水平上具有60-100%的同源性。
2.如权利要求1的nCL-3钙蛋白酶基因,其中,所述类似物具有截短的基因序列。
3.如权利要求1的nCL-3钙蛋白酶基因,该基因由序列6的序列编码。
4.一种含有权利要求1-3中任一项所述的nCL-3钙蛋白酶基因的基因结构,该结构与一个或几个调节信号功能性地连接,以加强该基因的表达。
5.一种由权利要求1所述nCL-3基因编码的氨基酸序列。
6.一种鉴定钙蛋白酶抑制剂的方法,其中,由权利要求1所述序列编码的钙蛋白酶是从能表达酶nCL-3的组织或细胞中提取的,检测到了试验物质对所述酶nCL-3的底物的裂解的抑制作用,而且在至少一种其它试验中,检测到了试验物质对所述钙蛋白酶I和/或II的底物的裂解的抑制作用,选择所述对至少一种钙蛋白酶具有抑制作用的试验物质。
7.如权利要求6的方法,其中,选择不能抑制酶nCL-3,但能抑制钙蛋白酶I和/或II的试验物质。
8.如权利要求6的方法,其中,选择能抑制酶nCL-3,但不能抑制钙蛋白酶I和/或II的试验物质。
9.如权利要求6-8中任一项所述的方法,其中,选择在细胞系统中能通过细胞膜的试验物质。
10.一种制备酶nCL-3的方法,其特征在于,该方法包括将一个拷贝的如权利要求1所述的nCL-3的基因序列克隆到一种载体中,并在适合该载体的宿主生物中由该基因表达酶nCL-3,然后从所述宿主生物中提取该酶。
11.如权利要求10的方法,其中,使用一种能够在原核或真核细胞中表达所述nCL-3基因的载体。
12.如权利要求10的方法,其中,将细菌、真菌或动物细胞用作宿主生物。
13.如权利要求10的方法,其中,将杆状病毒用作载体,并将昆虫细胞用作宿主生物。
14.将钙蛋白酶抑制剂用于生产用来治疗存在钙蛋白酶功能异常的疾病的药品的用途,所述钙蛋白酶抑制剂可以用权利要求6-9所述方法鉴定。
15.如权利要求14的钙蛋白酶抑制剂的用途,将其用于生产治疗选自下列一组的疾病的药品:心血管疾病、免疫学疾病、炎症、变态反应、神经病、神经变性疾病或致癌疾病。
16.将权利要求5所述的钙蛋白酶nCL-3用于试验系统的用途。
17.将权利要求5所述的钙蛋白酶nCL-3用于生产抗体的用途。
18.将权利要求1所述基因序列用于生产反义mRNA的用途。
19.将权利要求18所述反义mRNA用于生产治疗存在钙蛋白酶功能异常的疾病的药品的用途。
20.将权利要求1的钙蛋白酶基因用于诊断疾病或基因治疗的用途。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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DE19650142.3 | 1996-12-04 | ||
DE1996150142 DE19650142A1 (de) | 1996-12-04 | 1996-12-04 | Neue Calpaine, ihre Herstellung und Verwendung |
DE1997118248 DE19718248A1 (de) | 1997-04-30 | 1997-04-30 | Neue Calpaine, ihre Herstellung und Verwendung |
DE19718248.8 | 1997-04-30 |
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CN1245536A true CN1245536A (zh) | 2000-02-23 |
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CN97181646A Pending CN1245536A (zh) | 1996-12-04 | 1997-11-28 | 新型钙蛋白酶,其制备和用途 |
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US (1) | US6569665B1 (zh) |
EP (1) | EP0942995A1 (zh) |
JP (1) | JP2001506846A (zh) |
KR (1) | KR20000057365A (zh) |
CN (1) | CN1245536A (zh) |
AU (1) | AU737504B2 (zh) |
BR (1) | BR9713849A (zh) |
CA (1) | CA2274304A1 (zh) |
CZ (1) | CZ9902005A3 (zh) |
HU (1) | HUP0000498A3 (zh) |
IL (1) | IL129909A0 (zh) |
NO (1) | NO992690L (zh) |
WO (1) | WO1998024916A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104458709A (zh) * | 2013-09-12 | 2015-03-25 | 中国药科大学 | 一种筛选钙激活中性蛋白酶-1抑制剂高通量筛选方法 |
CN105334329A (zh) * | 2015-12-10 | 2016-02-17 | 中国农业科学院农产品加工研究所 | 钙蛋白酶磷酸化水平的测定方法 |
Families Citing this family (5)
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AUPQ656500A0 (en) * | 2000-03-28 | 2000-04-20 | Autogen Pty Ltd | A method of treatment and agents for same |
WO2005082860A1 (en) * | 2004-02-27 | 2005-09-09 | National Research Council Of Canada | Tetracyclines and their use as calpain inhibitors |
CA2631071A1 (en) * | 2008-05-09 | 2009-11-09 | Tong-Jun Lin | Inhibition of calpain reduces allergic inflammation |
WO2018071216A1 (en) * | 2016-10-11 | 2018-04-19 | University Of Iowa Research Foundation | Methods and compositions for treating genetic eye diseases |
WO2021072196A1 (en) * | 2019-10-11 | 2021-04-15 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions and methods for measuring and inhibiting calpain-5 activity |
Family Cites Families (2)
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ATE268816T1 (de) * | 1994-07-15 | 2004-06-15 | Cephalon Inc | In baculovirus exprimiertes aktives calpain |
EP0717110A1 (en) * | 1994-11-22 | 1996-06-19 | Association Francaise Contre Les Myopathies | LGMD gene |
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1997
- 1997-11-28 EP EP97952002A patent/EP0942995A1/de not_active Withdrawn
- 1997-11-28 IL IL12990997A patent/IL129909A0/xx unknown
- 1997-11-28 WO PCT/EP1997/006644 patent/WO1998024916A1/de not_active Application Discontinuation
- 1997-11-28 AU AU55576/98A patent/AU737504B2/en not_active Ceased
- 1997-11-28 JP JP52516098A patent/JP2001506846A/ja active Pending
- 1997-11-28 KR KR1019990704896A patent/KR20000057365A/ko not_active Application Discontinuation
- 1997-11-28 CA CA002274304A patent/CA2274304A1/en not_active Abandoned
- 1997-11-28 CN CN97181646A patent/CN1245536A/zh active Pending
- 1997-11-28 US US09/308,345 patent/US6569665B1/en not_active Expired - Fee Related
- 1997-11-28 CZ CZ992005A patent/CZ9902005A3/cs unknown
- 1997-11-28 BR BR9713849-5A patent/BR9713849A/pt not_active IP Right Cessation
- 1997-11-28 HU HU0000498A patent/HUP0000498A3/hu unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104458709A (zh) * | 2013-09-12 | 2015-03-25 | 中国药科大学 | 一种筛选钙激活中性蛋白酶-1抑制剂高通量筛选方法 |
CN105334329A (zh) * | 2015-12-10 | 2016-02-17 | 中国农业科学院农产品加工研究所 | 钙蛋白酶磷酸化水平的测定方法 |
Also Published As
Publication number | Publication date |
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WO1998024916A1 (de) | 1998-06-11 |
CZ9902005A3 (cs) | 1999-09-15 |
AU737504B2 (en) | 2001-08-23 |
EP0942995A1 (de) | 1999-09-22 |
HUP0000498A2 (hu) | 2000-06-28 |
AU5557698A (en) | 1998-06-29 |
BR9713849A (pt) | 2000-02-29 |
JP2001506846A (ja) | 2001-05-29 |
CA2274304A1 (en) | 1998-06-11 |
KR20000057365A (ko) | 2000-09-15 |
NO992690L (no) | 1999-08-03 |
HUP0000498A3 (en) | 2003-08-28 |
US6569665B1 (en) | 2003-05-27 |
NO992690D0 (no) | 1999-06-03 |
IL129909A0 (en) | 2000-02-29 |
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